Study sounds note of cautious hope for reversing Alzheimer brain damage
Shutting off production of tau, a protein implicated in Alzheimer's disease, reverses memory loss in aging mice and prevents further brain shrinkage and death of cells, even though the pathological structures associated with tau continue to form. These conclusions are reported by Karen Hsiao Ashe, M.D., Ph.D., and colleagues in the July 15 Science.
"Although we always have to be cautious about reading too much into an animal study, this work is noteworthy for two reasons," says William H. Thies, Ph.D., Alzheimer's Association vice president, medical and scientific affairs. "First, by actually improving memory and boosting cell counts, it suggests it may be possible to restore the function of cells that have been damaged but have not yet degenerated beyond repair. If this is true, it shifts our best case scenario for people with Alzheimer's from stopping further decline to actually recovering lost ground.
"Second, if meaningful improvement in function is a real possibility, that will make it much easier to test experimental treatments, since it's more straightforward and less costly to measure improvement than long-term stabilization of symptoms. That could accelerate drug development significantly."
In this study, researchers developed a mouse genetically engineered to produce a human form of Alzheimer tau (pronounced to rhyme with "wow"). Tau is a protein used by cells to construct microscopic "railroad tracks" to carry food and other "supplies" throughout the cell. In Alzheimer's and certain other disorders, tau loses its ability to form orderly tracks and twists into long fibers called tangles.
Scientists have long assumed that tangles kill cells by disrupting their internal supply chain, but results of this study challenge that assumption. In addition to the tau gene itself, these researchers installed a genetic switch that turns tau off when the mice are given food laced with the antibiotic tetracycline. Results suggest that after the mice pass the age of four months, tangles continue to form even after tau is turned off. Yet these mice also begin to perform better in memory tasks and have less brain shrinkage and more living cells than mice whose human tau gene remains in the "on" position.
These observations suggest that tangles may not be an important cause of memory symptoms or cell death. The real culprits could be individual tau molecules or small preliminary clumps, and the tangles may represent a cell's efforts to bundle up these smaller pieces and pull them out of circulation.
Two researchers involved in this work have received grants from the Alzheimer's Association for other aspects of their work. Principal investigator Karen Hsiao Ashe, M.D., Ph.D., received grants in 1989 and 1993 to develop mouse models producing human forms of other proteins associated with neurological disorders. In 1996, her University of Minnesota research team announced the first mouse model producing a form of human beta-amyloid, the other protein in addition to tau most closely associated with Alzheimer's disease. Bradley T. Hyman, M.D., Ph.D., received the Association's 2000 Pioneer Award in Alzheimer's Disease Research, also for work relating to mouse models of the disease.